Germline variants identified in patients with early-onset renal cell carcinoma referred for germline genetic testing Journal Article


Authors: Truong, H.; Sheikh, R.; Kotecha, R.; Kemel, Y.; Reisz, P. A.; Lenis, A. T.; Mehta, N. N.; Khurram, A.; Joseph, V.; Mandelker, D.; Latham, A.; Ceyhan-Birsoy, O.; Ladanyi, M.; Shah, N. J.; Walsh, M. F.; Voss, M. H.; Lee, C. H.; Russo, P.; Coleman, J. A.; Hakimi, A. A.; Feldman, D. R.; Stadler, Z. K.; Robson, M. E.; Motzer, R. J.; Offit, K.; Patil, S.; Carlo, M. I.
Article Title: Germline variants identified in patients with early-onset renal cell carcinoma referred for germline genetic testing
Abstract: BACKGROUND: Despite guidelines recommending genetic counseling for patients with early-onset renal cell carcinoma (RCC), studies interrogating the spectrum of germline mutations and clinical associations in patients with early-onset RCC are lacking. OBJECTIVE: To define the germline genetic spectrum and clinical associations for patients with early-onset RCC diagnosed at age ≤46 yr who underwent genetic testing. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively identified patients with early-onset RCC who underwent germline testing at our institution from February 2003 to June 2020. OUTCOME MEASUREMENT AND STATISTICAL ANALYSIS: The frequency and spectrum of pathogenic/likely pathogenic (P/LP) variants were determined. Clinical characteristics associated with mutation status were analyzed using two-sample comparison (Fisher's exact or χ2 test). RESULTS AND LIMITATIONS: Of 232 patients with early-onset RCC, 50% had non-clear-cell histology, including unclassified RCC (12.1%), chromophobe RCC (9.7%), FH-deficient RCC (7.0%), papillary RCC (6.6%), and translocation-associated RCC (4.3%). Overall, 43.5% had metastatic disease. Germline P/LP variants were identified in 41 patients (17.7%), of which 21 (9.1%) were in an RCC-associated gene and 20 (8.6%) in a non-RCC-associated gene, including 17 (7.3%) in DNA damage repair genes such as BRCA1/2, ATM, and CHEK2. Factors associated with RCC P/LP variants include bilateral/multifocal renal tumors, non-clear-cell histology, and additional extrarenal primary malignancies. In patients with only a solitary clear-cell RCC, the prevalence of P/LP variants in RCC-associated and non-RCC-associated genes was 0% and 9.9%, respectively. CONCLUSIONS: Patients with early-onset RCC had high frequencies of germline P/LP variants in genes associated with both hereditary RCC and other cancer predispositions. Germline RCC panel testing has the highest yield when patients have clinical phenotypes suggestive of underlying RCC gene mutations. Patients with early-onset RCC should undergo comprehensive assessment of personal and family history to guide appropriate genetic testing. PATIENT SUMMARY: In this study of 232 patients with early-onset kidney cancer who underwent genetic testing, we found a high prevalence of mutations in genes that increase the risk of cancer in both kidneys and other organs for patients and their at-risk family members. Our study suggests that patients with early-onset kidney cancer should undergo comprehensive genetic risk assessment. Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Keywords: kidney cancer; genetic counseling; early-onset renal cell carcinoma; germline sequencing; hereditary renal cell carcinoma syndromes
Journal Title: European Urology Oncology
Volume: 4
Issue: 6
ISSN: 2588-9311
Publisher: Elsevier BV  
Date Published: 2021-12-01
Start Page: 993
End Page: 1000
Language: English
DOI: 10.1016/j.euo.2021.09.005
PUBMED: 34654685
PROVIDER: scopus
PMCID: PMC8688197
DOI/URL:
Notes: Article -- Export Date: 1 February 2022 -- Source: Scopus
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MSK Authors
  1. Jonathan Coleman
    346 Coleman
  2. Sujata Patil
    511 Patil
  3. Paul Russo
    582 Russo
  4. Kenneth Offit
    790 Offit
  5. Robert Motzer
    1247 Motzer
  6. Mark E Robson
    681 Robson
  7. Darren Richard Feldman
    343 Feldman
  8. Zsofia Kinga Stadler
    393 Stadler
  9. Marc Ladanyi
    1332 Ladanyi
  10. Martin Henner Voss
    293 Voss
  11. Vijai Joseph
    212 Joseph
  12. Yelena Kemel
    104 Kemel
  13. Abraham Ari Hakimi
    327 Hakimi
  14. Maria Isabel Carlo
    165 Carlo
  15. Chung-Han   Lee
    157 Lee
  16. Michael Francis Walsh
    156 Walsh
  17. Diana Lauren Mandelker
    181 Mandelker
  18. Ozge Birsoy
    69 Birsoy
  19. Alicia Latham
    60 Latham
  20. Ritesh Rajesh Kotecha
    94 Kotecha
  21. Neil Jayendra Shah
    91 Shah
  22. Aliya Khurram
    22 Khurram
  23. Rania A Sheikh
    9 Sheikh
  24. Nikita Navinchandra Mehta
    16 Mehta
  25. Peter Anselm Reisz
    17 Reisz
  26. Andrew Thomas Lenis
    23 Lenis
  27. Hong Truong
    19 Truong